Osteoporosis in Breast and Prostate Cancer Survivors
Osteoporosis in Breast and Prostate Cancer Survivors
Recent advances in treatment modalities for breast and prostate cancer have resulted in an increasing number of patients that are cured or that, despite residual disease, live long enough to start experiencing complications from cancer treatment. Osteoporosis is one such problem that has been increasingly identified in cancer patients. Hypogonadism and glucocorticoid use are the two major causes of bone loss in these patients. Osteoporosis is characterized by low bone mass and abnormal bone microarchitecture, which results in an increased risk of fractures. Vertebral body and hip fractures commonly result in a drastic change of quality of life as they can result in disabling chronic pain, loss of mobility, and loss of independence in performing routine daily activities, as well as in increased mortality. In patients with prostate carcinoma, androgen-deprivation therapy by either treatment with a gonadotropin-releasing hormone (GnRH) or bilateral orchiectomy results in increased bone turnover, significant bone loss, and increased risk of fractures. Patients with breast cancer are at increased risk for estrogen deficiency due to age-related menopause, ovarian failure from systemic chemotherapy, or from the use of drugs such as aromatase inhibitors and GnRH analogs. Several studies have indicated that the prevalence of fractures is higher in breast and prostate cancer patients compared to the general population. Therefore, patients at risk for bone loss should have an assessment of their bone mineral density so that prevention or therapeutic interventions are instituted at an early enough stage to prevent fractures. This article will address the characteristics of bone loss observed in breast and prostate cancer patients and potential treatments.
Advances in the medical treatment of breast and prostate cancer have improved cure rates or disease-free survival. Increasing longevity has resulted in the emergence of medical problems associated with the malignancy or caused by the oncologic treatment. Bone loss is one such complication. In breast and prostate cancer patients, hypogonadism is the predominant cause of bone loss. In breast cancer patients, estrogen deficiency caused by premature ovarian failure, a result of systemic chemotherapy, or from drugs such as aromatase inhibitors or GnRH analogs causes bone loss.[1-5] Acute estrogen deficiency results in higher bone turnover and rapid bone loss, at a rate greater than that seen during natural menopause.[ 4] In patients with prostate cancer, hypogonadism as a result of androgen-deprivation therapy also leads to higher bone turnover, bone loss, and increased risk of fractures.[6-8] The aim of this review is to discuss the known frequency, magnitude, and mechanisms of bone loss observed in breast and prostate cancer patients, as well as to summarize the current recommendations on how to prevent bone loss or treat patients with osteoporosis. Definition and Diagnosis of Osteoporosis Osteoporosis is defined as a metabolic bone disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and increased risk of fractures. Vertebral body and hip fractures commonly result in a significant change in quality of life; they cause chronic pain, loss of mobility, and loss of independence in performing daily activities. Hip fracture is the most devastating complication of osteoporosis. Epidemiologic studies show clearly that survival probability is reduced dramatically, at any age over 60 years, suggesting that untreated osteoporosis could have an independent effect on survival in women with breast cancer. There are similar and even more striking results for men with hip or vertebral fractures. Therefore it is important to evaluate bone mass in hypogonadal patients and initiate therapy for those at risk. Bone mass can be measured by several noninvasive methods. These include dual-energy x-ray absorptiometry (DXA), quantitative computed tomography scan (QCT), and ultrasound. The method of choice is DXA, as it is easily accessible, provides low radiation exposure, and has good precision. It can be used to diagnose osteopenia or osteoporosis, to determine fracture risk, and to monitor response to therapy. The definition of normal bone mass, osteopenia, or osteoporosis is based on the World Health Organization (WHO) criteria. Risk is defined by comparing an individual patient's bone mineral density (BMD) with an age, sex, and ethnically appropriate population. Osteoporosis is defined as a BMD ≥ 2.5 standard deviations (SD) below average peak adult bone mass. This is designated as a T score of -2.5 or less (Table 1). A higher BMD, but one that is less than normal (-1 to -2.5), is defined as osteopenia. These patients do not currently have a greater risk of fractures, but nevertheless form a high-risk population for future fractures. Both DXA and QCT can measure BMD of the spine and hips (central DXA or QCT) or BMD of peripheral sites such as the forearm (pDXA or pQCT). Measurement of spine and hip BMD is the gold standard for diagnosis and monitoring of osteoporosis, while peripheral measurements are performed mainly for screening purposes. Quantitative computed tomography is a more sensitive but less precise method than DXA for diagnosing osteoporosis in men. In older men, osteophytes or facet sclerosis of the posterior elements may increase the spine BMD values. Therefore, whenever possible DXA measurements of other sites or QCT of the spine should be performed in older individuals. The most common cause of osteoporosis in women, including women with breast cancer, is estrogen deficiency. In postmenopausal osteoporosis, there is an increased rate of bone remodeling and an imbalance between bone resorption and bone formation that results in a net loss of bone.[13,14] Bone loss in postmenopausal women occurs in two phases.[ 15] In the first 5 years after menopause there is a rapid phase of bone loss (about 3%/yr in the spine) followed by a phase of slower rate of bone loss (about 0.5%/yr) that occurs not only at the spine but also at other sites. The slower phase of bone loss starts at around age 55 in both men and women. Other than gonadal function, vitamin D and calcium deficiencies are common problems in older individuals.[ 15] Approximately 30% to 50% of older individuals have subnormal plasma vitamin D concentration. Other contributors to bone loss in cancer patients that are less well-defined include direct effects of chemotherapy agents on bone cells, reduced physical activity, exposure to corticosteroids, and deficient dietary calcium intake. It is important for the oncologist or internist following this group of patients to recognize that it is a series of small but additive medical and lifestyle changes that contribute to the steady decline in bone mass. The corollary is that it is not inevitable: simple preventive measures will have profound long-term effects. The increased bone remodeling in sex steroid hormone deficiency causes deregulation of cytokines, hormones, and growth factors present in the bone microenvironment. These changes result in activation of osteoclastic bone resorption and bone loss. To better understand the mechanisms of bone loss and the rationale for the use of specific pharmacologic agents to prevent and treat osteoporosis, we will discuss how bone is remodeled in normal and sex steroid-deficient states. Bone Remodeling The adult skeleton is in a dynamic state, constantly being renewed in a continuous and coordinated fashion throughout life to maintain the structure and quality of bone. Bone remodeling, also termed bone turnover, occurs simultaneously in tens of thousands of skeletal areas. Each of these areas is called a bone-remodeling unit. The initiating event in remodeling at each of these bone-remodeling units is the differentiation of monocytic cells into multinucleated cells called osteoclasts. These cells bind tightly to bone, produce acid and proteolytic enzymes, and cause the resorption of mineral and bone protein, creating a resorption lacuna of uniform size and depth. The osteoclast is then replaced with scavenger cells to clean up resorbed material, followed by osteoblasts or bone-forming cells. These cells lay down multiple layers of type 1 collagen that is mineralized to form new bone. This entire process takes 3 to 4 months. Most importantly, this process makes it possible to repair microfractures that result from normal minor trauma or other "wear and tear" to the skeleton. Normal bone remodeling is a balanced event: bone resorption is equaled by bone formation. The remodeling process occurs under control of several hormones and cytokines that are active within the bone microenvironment. These include estrogen, testosterone, parathyroid hormone, and growth hormone. Other important factors include vitamin D, interleukins (IL-1, IL-4, IL-6, IL-7, IL-11, IL-17), transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), prostaglandin E2, and the receptor activator of nuclear factor kappaB ligand (RANKL).[17,18] RANKL is a critical cytokine for osteoclastogenesis. It is expressed by osteoblasts and binds to the receptor activator of nuclear factor kappaB (RANK) present on the surface of osteoclasts precursors and mature osteoclasts. The RANKL/RANK interaction is responsible for differentiation of monocytes to osteoclasts and activates bone resorption by the mature osteoclast. Osteoprotegerin (OPG) is a decoy receptor, expressed by osteoblasts, that binds RANKL thereby preventing RANKL from activating RANK. The balance between RANKL and OPG is essential for normal bone remodeling. Overexpression of RANKL will result in increased bone resorption and osteoporosis; overexpression of OPG will result in inhibition of bone resorption and osteopetrosis. Alteration in the RANKL/OPG ratio has been observed in several conditions associated with osteoporosis, including estrogen deficiency, corticosteroid use, hyperparathyroidism, rheumatoid arthritis, multiple myeloma, osteolytic bone metastases, and humoral hypercalcemia of malignancy.[ 18] In most of these disorders there is overexpression of RANKL and decreased production or increased degradation of OPG. Estrogen deficiency can result in an increase of the RANKL/OPG ratio. Eghbali-Fatourechi and colleagues showed that the RANKL level was higher in marrow stromal cells and lymphocytes of postmenopausal women as compared to premenopausal women; RANKL expression was inversely correlated with estrogen levels.[ 20] These findings demonstrate the important role of the OPG/ RANKL/RANK system in mediating estrogen deficiency-induced bone resorption. As estrogen deficiency is the main cause of bone loss in breast cancer patients, one could postulate that the OPG/RANKL/RANK system plays an important role in the mechanism of bone loss in these patients. In fact, the effect of a monoclonal antibody against RANKL, which functions to prevent the RANKL-RANK interaction, is under investigation as a therapeutic agent to inhibit bone loss in estrogen-deficient breast cancer patients. In clinical practice, bone resorption and formation are easily quantified. Table 2 shows several readily available markers of formation and resorption. The formation markers include bone proteins incorporated into the matrix (osteocalcin or collagen) or enzymes involved in mineralization (alkaline phosphatase). All bone resorption markers are fragments of bone-specific collagen released by the osteoclast. Bone Loss in Breast Cancer Patients Breast cancer is the most common malignancy in women, with an estimated 40,410 new cases in the United States predicted for 2005. Early detection and improved treatment modalities have resulted in a significant improvement of disease-free and overall survival. More than 90% of patients with early-stage breast cancer are alive 10 years after diagnosis, a survival improvement that is mainly due to advances in adjuvant chemotherapy and radiation therapy. Unfortunately, adjuvant systemic chemotherapy can induce ovarian failure in premenopausal patients with early breast cancer and exacerbate the expected bone loss in postmenopausal patients. Premature menopause occurs in 50% to 85% of patients treated with adjuvant chemotherapy regimens that include cyclophosphamide, metho trexate, fluorouracil, and doxorubicin.[ 1] The effect of chemotherapy (cyclophosphamide-based) on ovarian function is dose- and age-dependent. The frequency of ovarian failure rises as patients approach the natural age of menopause, reaching nearly 100% by the age of 50 years. A few studies have investigated the magnitude and frequency of bone loss in patients undergoing adjuvant chemotherapy (Table 3). All highlight the tight correlation between development of ovarian failure and bone loss. Shapiro and colleagues investigated the BMD and markers of bone turnover (osteocalcin, bone alkaline phosphatase) at baseline, 6 months, and 12 months in 49 patients receiving adjuvant systemic chemotherapy. Patients who developed ovarian failure lost 4% BMD in the lumbar spine at 6 months and an additional 3.7% bone loss at 12 months. The bone loss was accompanied by a significant increase of serum osteocalcin and bonespecific alkaline phosphatase. In contrast, no significant bone loss was observed in patients who had maintained normal ovarian function. This has been corroborated in other studies. Headley and colleagues evaluated 27 patients with breast cancer treated with adjuvant chemotherapy who were premenopausal at the time of diagnosis. The BMD was assessed 2 years after treatment with adjuvant chemotherapy. Patients who became amenorrheic (16) had a BMD 14% lower than patients with intact ovarian function. Another study by Vehmanen and colleagues evaluated the long-term impact of chemotherapy-induced ovarian failure on bone mineral density.[ 3] This study involved 75 patients who received adjuvant chemotherapy for breast cancer. Patients who developed ovarian failure suffered a 12% reduction of lumbar spine BMD 5 years later, while patients who maintained gonadal function lost 3%. Most of the other studies are retrospective and involved fewer numbers of patients. Collectively, these studies have included a small number of patients followed for short periods; accordingly there is no substantial information on fracture prevalence in this group of patients. One study by Kanis and colleagues[ 24] investigated the incidence of osteoporotic fractures in patients with breast cancer as a subprotocol of two trials designed to assess the effect of clodronate on the incidence of skeletal metastases. The authors followed three groups of patients for 3 years: newly diagnosed breast cancer patients (356), healthy controls (776), and patients presenting with soft-tissue recurrence (82). They performed x-rays of the spine at baseline and every 6 months. The annual incidence of vertebral fracture was higher in any of the breast cancer groups compared to healthy controls: 19% in patients with recurrent disease, 2.7% in patients presenting with newly diagnosed disease, and 0.5% in controls. Adjuvant hormonal treatment has resulted in significant improvement in disease-free and overall survival for women with hormone receptor- positive breast cancer. For several years tamoxifen was the standard hormonal treatment in postmenopausal women. Recently, several multicenter, randomized, phase III adjuvant trials have compared the new generation of aromatase inhibitors to tamoxifen or placebo following tamoxifen therapy (5 or fewer years). These trials include the ATAC trial, comparing initial therapy with anastrozole (Arimidex) to tamoxifen; the MA- 17 trial, which evaluated the effects of letrozole (Femara) vs placebo after 5 years of tamoxifen; and the Intergroup Exemestane Study, which included women treated with tamoxifen for 2 to 3 years, randomized to complete 5 years of tamoxifen or 2 to 3 years of exemestane (Aromasin).[ 28] In all of these trials, treatment with an aromatase inhibitor was superior to tamoxifen, providing a lower risk of tumor recurrence and better disease-free survival. Treatment with aromatase inhibitors rather than tamoxifen has become the preferred primary form of therapy for women with hormone receptor- positive breast cancer. As the aromatase inhibitors cause a marked reduction in the circulating levels of estrogen, it is expected that they will exacerbate bone loss in postmenopausal patients. This is of concern as many of these patients have already suffered accelerated bone loss from premature menopause, and rather than being treated with tamoxifen-a drug that maintains bone mass in postmenopausal women-are placed on aromatase inhibitors that result in further bone loss. Information regarding the effects of aromatase inhibitors on bone mass is still limited. The best information available to date can be obtained from a substudy of the ATAC trial. In this study 308 patients underwent a BMD study at baseline and after 1 and 2 years of treatment. Patients who received anastrozole lost 4% of bone mass at the lumbar spine at 2 years while no bone loss was observed in other groups. In addition, the number of fractures was higher in patients who received anastrozole. Therefore, in contrast to tamoxifen, which has beneficial effects to the bone mass of postmenopausal women,[29-31] anastrozole has been shown to result in bone loss and to increase the risk of fractures.